DE3330403A1 - BENZAMIDE DERIVATIVES - Google Patents

Description

Case 973

MAY & BAKER LIMITED Dagenham, Essex / England

Benzamide derivatives

description

The present invention relates to new, therapeutically valuable benzamide derivatives and processes for their preparation and pharmaceutical compositions containing them.

The benzamide derivatives of the present invention are compounds of the general formula I.

(D

CONH A N

where mean:

A is a divalent, straight or branched chain alkylene group with 1 to 6 and preferably 2, 3 or 4 carbon atoms;

R is a halogen atom, i.e. fluorine, chlorine, bromine or iodine atom, or a hydroxy, mercapto, amino, Nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl (e.g. trifluoromethyl), Alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, Alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, Dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino group;

m is O or the number 1, 2 or 3;

ρ
R represents a hydrogen atom or an alkyl group;

■ 5
R is a halogen atom or a hydroxy, amino,

Nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl (e.g. trifluoromethyl), Alkoxy, alkoxycarbonyl, dialkylamino, alkylcarbamoyl or alkanoylamino group;

η O or the number 1 or 2; R is an alkyl radical; and

ρ O or the number 1 or 2, as well as pharmaceutically acceptable salts thereof.

Fluorine-substituted alkyl groups within the definition of the substituents R and R- ^ can be replaced by one or more Fluorine atoms may be substituted. The above alkyl groups or parts, alkoxy groups or parts, and alkanoyl groups or parts can be straight or branched chain and have 1 to 10 (preferably 1 to 4) carbon atoms contain. The alkyl parts in the above dialkylamino and dialkylcarbamoyl groups can be the same or be different from each other.

If any of the symbols m, η and ρ means the number 2 or 3, the corresponding Symbol R, R ^ or R represented groups the same or to be different.

1 2 ³ J In certain cases the substituents R, R, R, R and the alkylene group A contribute to optical isomerism. All such forms are encompassed by the present invention.

By the term "pharmaceutically acceptable salt" in relation to the compounds of general formula I. is to be understood as a salt which, by reaction with an acid or, if R or R denotes a carboxyl group, is formed by reaction with a base, so that the anion (in the case of an acid addition salt) or the cation (in the case of a salt formed by a compound of the general formula I in which R or R is a Means carboxyl group is formed) is relatively harmless to the animal organism if it is used in therapeutic dosages, so that the beneficial pharmacological properties of the Parent compound of the general formula I by side effects which can be ascribed to this anion or cation would not be affected.

Suitable acid addition salts include salts derived from inorganic acids, e.g. hydrochlorides, hydrobromides, Phosphates, sulfates and nitrates, and organic salts, e.g. methanesulfonates, 2-hydroxyethanesulfonates, Oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, Maleates, methylene-bis-ß-hydroxynaphthoates, gentisates and di-p-toluoyltartrates.

Suitable salts which are formed by compounds of the general formula I in which R or R ^ are a carboxyl group include the alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts and salts of amines, the are known to be pharmaceutically acceptable in the art, e.g., ethylenediamine, chcline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2- (hydroxymethyl) propane-i, 3-diol and 1- (3,4-dihydroxyphenyl ) -2-isopropylaminoethanol.

It should be noted that when in the present specification reference is made to the compounds of general formula I, including their pharmaceutically acceptable ones Salts, as indicated above, should be referred to when the context allows.

Preferred compounds of the general formula I are those in which A is an ethylene, trimethylene, 3-methyltrimethylene or tetramethylene group and R is a halogen atom or an amino, nitro, trifluoromethyl or acetamido group or an alkyl, e.g. methyl, Alkoxycarbonyl or C _-1 ^ alkoxy group means

P tet and m stands for 0 or the number 1, 2 or 3, R is a hydrogen atom, R is a halogen atom, preferably Chlorine atom, and η is 0 or the number 1, and R is an alkyl, e.g., methyl, group in 2- or 4-position and ρ for O or the number 1 stands.

Particularly preferred compounds of the general formula I are those in which A is an ethylene, trimethylene or 3-methyltrircethylene group, R is a halo

genatom, a trifluoromethyl group or an alkyl group, e.g. methyl, and m for the number 1

2 ^ 5

or 2, R is a hydrogen atom, R- ^ is a Represents halogen atom, preferably chlorine, and η represents 0 or the number 1, R represents an alkyl group, e.g. Is methyl, in the 4-position and ρ represents 0 or the number 1. If m is 1, the group is R preferably in the 2-, 3- or 4-position or in the 3-position, when R represents a trifluoromethyl group. If m stands for the number 2, then the groups are R. preferably the same and in the 2,4-, 3,4- or 2,5-position, if they are halogen atoms, and in the 3,4-position, if they are methyl groups. The symbol A preferably means trimethylene.

The compounds of general formula I have valuable pharmacological properties, in particular hypoglycemic activity, and some are intermediate compounds for the production of other therapeutically valuable derivatives. The connections of the general Formula I lower the blood glucose level in mice suffering from diabetes mellitus. You humiliate them Concentrations of cholesterol and triglycerides in the blood. They are thus of value in prevention or Treatment of diabetes mellitus, hyperlipoproteinemic conditions and arteriosclerosis.

Compounds of general formula I which are of particular interest include the following compounds and their salts.

link

A 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

B 2- (3-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

C2- (2-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

D 2- (4-bromobenzenesulfonamido) -N- (3-imidazol-1-ylpropyl) -benzamide

E 2- (Benzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

F 2- (4-methylbenzenesulfonamido) -ü- (3-imidazo 1-1-yl-propyl) -benzamide

G 2- (3,4-Dimethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

H 2- (4-nitrobenzenesulfonamido) -N- (3-imidazc 1-1-ylpropyl) -benzamide

I 5 -Chlor-2- (4-chlorobenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

J 2- (2,5-dichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

K 2- (2-Nitrobenzenesulfonamido) -N- (3-imidazol-1 -ylpropyl) -benzamide

L 2- (4-fluorobenzenesulfonamido) -N- (3-imidazol-1-ylpropyl) -benzamide

M 2- (4-chlorobenzenesulfonamido) -N- [3- (2-methylimidazol-1-yl) propyl] benzamide

N 2- (4-chlorobenzenesulfonamido) -N- [3- (4-methylimidazol-1-yl) propyl] benzamide

O 2- (4-nitrobenzenesulfonamido) -N- [3- (4-methylimidazol-1-yl) propyl] benzamide

P 2- (4-aminobenzenesulfonamido) -N- (3-imidazo1-1-ylpropyl) -benzamide

Q 2- (4-Methoxybenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

R 2- (4-acetamidobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

- ΛΛ ·

S 2- (4-Isopropylbenzenesulfonamido) -N- (3-imidazol- 1-yl-propyl) -benzamide

T 2- (4 ^ -t-butylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

U 2- (4-octylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

V 2- (4-ethoxycarbonylbenzenesulfonamido) -N- (3- imidazol-1 -yl-propyl) -benzamide

¥ 2- (3-Trifluoraethylbenzenesulfonamido) -N- (3- imidazol-1 -yl-propyl) -benzamide

X 2- (3 »4-dichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

Y 2- (2,4-dichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

Z 2- (2,6-dichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

AA 2- (2,3-dichlorobenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide

BB 2- (2-trifluoromethylbenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide

CC 2- (4-chloro-2-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide DD 2- (3,5-bis-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide EE 2- (2,4,5-trichlorobenzenesulfonamido) -N- (3-imidazole -1-yl-propyl) -benzamide

FF 2- (2,3,4-trichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

GG 2- (4-chloro-3-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide HH 5-chloro-2- (3-trifluoromethylbenzenesulfonamido) -N- (3-imidazole-1- yl-propyl) -benzamide II 5-chloro-2- (3,5-bis-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

JJ 5-chloro-2- (3-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

KK 2- (3-fluorobenzenesulfonamido) -N- (3-imidazol-1-ylpropyl) -benzamide

LL 2- (3-Fluoro-4-methylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

MM 2- (3-bromobenzenesulfonamido) -N- (3-imidazo1-1-ylpropyl) -benzamide

NN 2- (3-nitrobenzenesulfonamido) -N- (3-imidazol-1-ylpropyl) -benzamide

00 2- (2,4-Difluorobenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide

PP 2- (3-methylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

QQ 2- (2-Methylbenzenesulfonamido) -N- (3-imidazol-iyl-propyl) -benzamide

PiR 2- (2-fluorobenzenesulfonamido) -N- (3-imidazol-1-ylpropyl) -benzamide

SS 2- (2-chloro-5-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide

TT 2- (4-iodobenzenesulfonamido) -N- (3-imidazol-1-ylpropyl) -benzamide

UU 2- (4-Chlorobenzenesulfonamido) -N- (4-imidazo1-1-y1-butyl) -benzamide

VV 2- (4-chlorobenzenesulfonamido) -N- (2-imidazol-1-ylethyl) -benzamide

WW 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-ylbutyl) -benzamide.

The letters A to WW are assigned to the compounds for reference in the further description, for example in the following tables to facilitate.

Λ3

The compounds A, ¥ and W hydrochloride are preferred Compounds according to the invention.

The pharmacological properties of the compounds of the general formula I or their salts were shown in the following tests.

Hypoglycemic activity in diabetic mice

Diabetic egg mice (strain C 57, black, MRI, derived from Obese / Obese) of both sexes, each weighing between 45 and 70 g, were given the test compound orally in tragacanth gum solution at a dose of 5, 10, 30, 100, 200 or 500 mg / kg Body weight / day administered for 3 days. 3 hours after the last dose, the animals were sacrificed with carbon dioxide and bled by cardiac puncture.

The blood glucose levels were determined by the GOD-Perid glucose oxidase method.

Control groups (which dosages of not using drug added tragacanth gum solution) were included in each test.

The percentage reduction in the concentration of blood glucose was determined by comparison with the simultaneous Controls calculated for each of the test compounds used.

The results are shown in Table I below.

- 333ο4ο3

Table I.

Compound mg / kg body weight % change in blood glucose weight / day compared to the control

group

A 200; 100; 30th -67 -61; -49; -13 P 200 -32 B 200 -60 G 200 -25 I 200 -57 J 200 -42 N 200 -48 YY 200 -53 W 200 -24 V 200 '■ -68 W 500; 200; 100; J ₁ O ; 10; 5
hydrochloride -46; -62; -50; -58; -29; -25 X 200 -58 Y 200 . -51 00 200 -35 QQ 200 -43

Hypoglycemic activity in diabetic mice

Groups of diabetic mice (strain C 57, black, MRI, derived from Obese / Obese) with male sex an average weight of 43 to 46 g, the test compound W hydrochloride was administered orally in tragacanth mucus lozenges

solution at a dose of 2, 5 or 100 mg / kg body weight / day administered for 8 days. 3 hours after the last dose, the animals were bled from the tail vein.

The blood glucose levels were determined by the glucose oxidase method determined by GOD-Perid.

Control groups (given undrugged tragacanth mucus solution) were given to each Test included.

The percentage reduction in the concentration of blood glucose was determined by comparison with the simultaneous Controls calculated. The results obtained are summarized in Table IA below.

Table IA

Dose mg / kg body weight % change in blood glucose weight / day compared to the control

sample

2 -25

5 -28

100 -50

Hypoglycemic activity in fasted rats

Rats (Sprague-Dawley) male with one each weight between 171 and 174 g received the test compound W hydrochloride orally in tragacanth mucus in a dose of 100 mg / kg body weight / day for 4 days. 4 hours after the third dose, the animals became left without food up to and after the fourth dose. 3 hours after the last dose, the animals were turned off the caudal vein bled out.

- From

The blood glucose levels were determined by the glucose oxidase method from GOD-Perid.

Control groups (given doses of un-druged tragacanth solution) were given included with every test.

The percentage reduction in the concentration of blood glucose was determined by comparison with the simultaneous Controls calculated. The results obtained are shown in Table IB below.

Table IB

Dose mg / kg body weight % change in blood glucose weight / day compared to the control

100 -26

Hypolipidemic activity in rats

Male VTistar rats of each weight from 120 to 150 g were caged in groups of eight and received a pelleted diet with 0.5% Weight / weight Cholesterol and 0.25% w / w. Cholic acid for 10 days. During the last 3 days of this During the period, the test compound was administered orally at a dose of 30, 100 or 200 mg / kg body weight / day in tragacanth mucus administered.

At noon on the 10th day, the animals were sacrificed by inhaling carbon dioxide from solid carbon dioxide. A blood sample was drawn by cardiac puncture and the serum cholesterol and serum triglycerides were determined analyzed by means of an auto-analyzer.

* ' " from

Control groups (who received doses only / unmedicated tragacanth mucus) became included with every test.

The percentage reductions in the concentration of serum cholesterol and serum triglycerides were made calculated by comparison with the simultaneous controls for each concentration of test compound used. The results obtained are shown in Table II below.

Table II

Compound mg / kg body % change in serum, compared with the control weight / day

Cholesterol triglycerides

A 200 -82, -82, -83 -85, -89, -75

100 -35 +36

30 -13 +67

D 200 -63 -59

E 200 -31 +55

F 200 -72 -60

The usefulness of the compounds is enhanced by the fact that they have a very low toxicity as can be seen from the following test.

Oral toxicity in mice

Groups of mice received orally measured doses of the test compound (in a 0.5% w / v aqueous suspension of tragacanth mucus) and were observed for 3 days thereafter. The percentage of animals which died at each dose during that period, was used to create a graphical representation of the Iaj ₀ * ^{h d} * · ^{O s} nige dose in mg / kg body weight, on the death of 50 % of mice leads is calculated.

The compounds of the invention were tested and the LD _{50 of} each compound was greater than 1000 mg / kg body weight.

The compounds of general formula I can be prepared are carried out by applying or adapting known methods (i.e. methods that have previously been used or in chemical literature), for example as indicated below.

(A) According to one feature of the present invention, the compounds of general formula I are prepared by reaction of a compound of the general formula II

(K ⁴ )]

CCHH-AH _n ^ H _(II)

(wherein A, R ² , R ^, R, η and ρ are as defined above) with a sulfonating agent of the general formula III

^ -SO ₂ -HaI (III)

wherein R ¹ and m are as defined above and Hal is a halogen atom, preferably chlorine.

The above reaction is generally carried out in water or an organic solvent, optionally in the presence of a Bas ^ _f z, p. one. Tr ^ alky! Amines * such as triethylamine, or fr ^ ridins ». Carried out at a temperature between ⁰ ° C. and the reflux temperature of the reaction mixture. An excess of? Ase can be considered as. Solvent to serve for the reaction. _^; ,. _T ...-.-. _: - _; ■ - _Ί : _r

(B) According to a feature of the present ..weiteren _w jve be the _invention; rbindu | jgen. dep .general; Formally I produced by!. ^ Reaction of a derivation of the general formula IV _s -,. ^ ,. _: τ

COOH

/ 1 2 "5 *

(where R, R, R, m and: η as defined above are) or a reactive derivative thereof, e.g. in * s * lfcu; ^ er ^ s; Mi3ifc): - M3 ^ ie ^ general formula V

(ν)

(v ^ brin A, R and ρ are defined as above).

The above., Reaction; Srird: stm? IälllgeÄedlne ^ ln ^ an "inert, organic solvent, e.g. dimethylformamide or dioxane, and preferably in the presence of an acid-binding agent By means of, for example, a trialkylamine such as triethylamine, performed at a temperature higher than

Ambient temperature can be, for example between 10 and 50 ⁰ C.

The acid chloride can be obtained by reacting a compound of the general formula IV with thionyl chloride by means of An Application or adaptation of methods known per se can be made.

The compounds of the general formula II can be prepared by reacting a compound of general formula V with a compound of general formula VI

(in which R, Bp and η are as defined above) or a compound of the general formula VII

α COOH "" · ■ (VII) N-H

κ-

(wherein R, R and η are as defined above) or a reactive derivative such as the acid chloride thereof in a manner similar to that described in (B) above is.

The compounds of the general formula IV can be prepared are by reaction of a compound of the general formula III with a compound of the general

- rf -

mean formula VII in a manner similar to that described above under (A).

The compounds of the general formulas III, V, VI and VII are known compounds or can be through Application or adaptation of known methods can be established.

According to a feature of the present invention, the compounds of general formula I are in their phar pharmaceutically acceptable salts and, vice versa, by applying or adapting known methods. This procedure is useful both as such and for the purification of compounds of general Formula I and its salts, taking advantage of the differences in solubility in water and various organic solvent of the compounds and their salts and any impurities present by means of known methods, such as crystallization, is exploited.

(i) Compounds of the general formula I in which R or R ^ is a carboxyl group can converted into their salts of pharmaceutically acceptable bases, e.g. B. by reaction with the appropriate Base, such as the appropriate amine or a compound of the general formula VIII

M ¹ OR (VIII)

(where M represents an alkali metal atom such as sodium or potassium, and R is an alkyl group with up to 4 carbon atoms, e.g. methyl or ethyl, or a Means hydrogen atom) in a suitable solvent, e.g. methanol or ethanol, or in a

-Z-

mixture of water and acetone; then, if necessary, by evaporating some or all of the solvent and collecting the solid salt.

These salts can be found in the parent compounds of the general Formula I can be converted, for example by reaction with a suitable acid, e.g. glacial acetic acid, in solution in a suitable solvent, e.g. water or ethanol, and then, if necessary, by evaporating some or all of the solvent and collecting the solid compound of the general Formula I.

(ii) Compounds of general formula I can be converted into their pharmaceutically acceptable acid addition salts be converted, for example by reaction with the appropriate acid in solution or suspension in a suitable solvent such as acetone, methanol or ethanol and then, if necessary, through Evaporate some or all of the solvent and collect the solid salt.

The acid addition salts can be converted into the parent compounds of the general formula I, for example by reaction with aqueous ammonia in the presence of a suitable solvent, e.g. B. Ethanol, and then by treatment with a weak acid, e.g. glacial acetic acid.

It should be noted that in carrying out the above-described methods in accordance with the invention it is desirable can be to introduce chemical protecting groups into the reactants in order to avoid side reactions, for example in the methods of producing the

derivatives described above can have hydroxy substituents within the definition of groups R and R, as defined in relation to general formula I, in benzyloxy groups before the reaction, as described, have been transferred, and subsequently removal of the benzyl protective groups.

It should be mentioned that the amino, alkylamino, carboxy and hydroxy groups present in certain reactants by any protecting group, which Usually used to protect amines, carboxylic acids or alcohols and their use the rest of the molecule is not adversely affected, can be protected.

The following examples are given:

The amino \ χηά alkylamino groups can be protected by residues such as tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, chloroacetyl or trityl;

the carboxyl groups can be protected by radicals such as methoxymethyl, tert-butyl, benzhydryl, p-nitrobenzyl or p-methoxybenzyl; and

the hydroxyl groups can be protected by radicals such as benzyl, trityl, tetrahydropyranyl or 2-methoxyprop-2-yl.

The various protective residues can be at the same time or removed sequentially.

The following can be mentioned as examples:

1330403

-, 23 -

(1) The removal of the protecting groups from amines is effected as follows:

In the case of a tert-butoxycarbonyl, trityl or p-methoxybenzyloxycarbonyl radical, by treatment in an acidic medium. Trifluoroacetic acid is preferably used and the process is carried out at a temperature between 0 and 20 ⁰ C, or anhydrous or aqueous formic acid or p-toluenesulfonic acid or methanesulfonic acid is used in acetone or acetonitrile at a temperature between 20 ⁰ C and the reflux temperature of the reaction mixture. Under these conditions, the compound of general formula I can be obtained in the form of the trifluoroacetate, the solvate with formic acid, the methanesulphonate or the p-toluenesulphonate, and the amine group can be released from these by any method which leads to the preparation of an amine from one of its salts is known, without affecting the rest of the molecule. In particular, the process is carried out by bringing the compound into contact with an ion exchange resin or by the action of an organic base.

In the case of a 2,2,2-trichloroethoxycarbonyl or p-nitrobenzyloxycarbonyl radical by reduction (especially by treatment with zinc in acetic acid).

In the case of a chloroacetyl or trichloroacetyl radical using that described in GB-PS 1,454,589 Method.

In the case of a benzyl, dibenzyl or benzyloxycarbonyl radical by catalytic hydrogenation.

- is-

In the case of a trifluoroacetyl residue, by treatment in a basic medium.

(2) The removal of the protecting groups from the carboxyl residue is effected as follows:

In the case of a tert-butyl, p-methoxybenzyl or benz hydryl residue by treatment in an acidic medium among those above for the removal of the trityl protective residue conditions described from an amino group. In the case of the benzhydryl radical, the process in In the presence of anisole.

In the case of a methoxymethyl group by treatment in a dilute, acidic medium.

In the case of a p-nitrobenzyl group by reduction (especially by treatment with zinc in acetic acid or by hydrogenolysis).

(3) The removal of the protective groups from the hydroxy radicals is effected as follows:

In the case of a benzyl, trityl or tetrahydropyranyl group by acidolysis, for example with trifluoroacetic acid, aqueous or non-aqueous formic acid or p-toluenesulfonic acid.

In the case of the 2-methoxy-prop-2-yl group, according to the method described in GB-PS 2,021,561.

It should be noted that it may be desirable to change the nature of one or more of the substituents in an appropriate one To change stage during the synthesis of the compounds according to the invention, for example the

-ΛΑ- 13

bonds of the general formula I, in which R or R means an amino group can alternatively be prepared are made from the corresponding connections of the

1 ^

general formula I, wherein R or R- 'is a nitro group means by applying or adapting methods known for such conversion. links of the general formula I, in which R or R is an amino group, can be converted into diazonium salts which can be used in the synthesis as described by Morrison and Boyd's "Organic Chemistry" (1959), and then into an iodine atom, for example.

The following examples and reference examples illustrate the preparation of the compounds according to the invention.

example 1 Connection A

32.9 g of 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide was dissolved in 165 ml of pyridine and 41.2 g of 4-chlorobenzenesulfonyl chloride was added in portions. The temperature of the reaction mixture rose to 52 ^° C. The solution was stirred at room temperature for 4 h and then poured into 1.5 1 of water in order to precipitate an oil which slowly solidified on standing. The solid was collected, washed with water and recrystallized from ethanol, yielding 24.4 g of 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide as a white solid, m.p. to 177 ⁰ C.

(i) The 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide used as the starting material above became manufactured as follows.

. AT·

22.0 grams of isatoic anhydride were added in portions to a stirred solution of 17.2 grams of 3-imidazol-1-yl-propylamine given in 100 ml of dioxane for 15 min. Stirring was continued for 40 minutes before the solution was im Was evaporated in vacuo to give 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide as a brown-yellow solid that was used without further purification.

Examples 2 to 12

If in a similar manner to example 1 for the Preparation of 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-y1-propyl) -benzamide is described, worked, but the 4-chlorobenzenesulfonyl chloride or replaced the 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide with the indicated starting materials, so were the following compounds of general formula I were prepared (the letter of the compound is in Brackets).

2 (B): 2- (3-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, mp 139-142 ° C): starting material, 3-chlorobenzenesulfonyl chloride;

3 (C): 2- (2-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, melting point 154 ° to 158 ° C.): starting material, 2-chlorobenzenesulfonyl chloride;

4 (D): 2- (4-Brombenzolsulfonamido) -N- (3-imidazol-1-y1-propyl) benzamide (white solid, mp 178-180 ⁰ C.): Starting material, 4-bromobenzenesulfonyl chloride;

5 (E): 2- (Benzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, m.p. 112 to 114 ° C): starting material, benzenesulfonyl chloride;

6 (F): 2- (4-methylbenzenesulfonamido) -N- (3-imide azol-1-yl-propyl) -benzamide (off-white solid, m.p.

147 to 149 ⁰ C): starting material ^ -Methylbenzenesulfonylchlorid;

7 (G): 2- (3,4-diss ⁱ ethylbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, m.p. 172 to 174 ⁰ C.): Starting material, 3,4 -Dimethylbenzenesulfonyl chloride;

8 (H): 2- (4-Nitrobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (fawn-colored solid, m.p.

148 to 15O ⁰ C): starting material, 4-nitrobenzenesulfonyl chloride;

9 (I): 5-chloro-2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, m.p. 125 to 128 ⁰ C.): Starting material, 5-chloro -2-amino-N- (3-imidazol-1-yl-propyl) -benzacid;

10 (J): 2- (2,5-Dichlorbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (light brown solid, mp 198-200 ⁰ C.): Starting material, 2,5-dichlorobenzenesulfonyl ;

11 (K): 2- (2-Nitrobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (light brown solid, melting point 145 to 147 ° C.): starting material, 2-nitrobenzenesulf onyl chloride;

12 (L): starting material, 4-fluorobenzenesulfonyl chloride: 2- (4-Fluorbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, mp 117-118 ⁰ C.).

Example 13 Connection M

10.5 g of 2-amino-N- [3- (2-methylimidazol-1-yl) propyl] benzamide were dissolved in 50 ml of pyridine and 12.35 g of 4-chlorobenzenesulfonyl chloride were selected in portions

-25 -

added for 5 min. The temperature of the reaction mixture rose to 45 ^° C. The solution was stirred for 4 h at room temperature and the pyridine was evaporated in vacuo to give a brown oil. The oil was chromatographed on silica gel, eluted with a mixture of chloroform and methanol (19: 1) to give 7 g of 2- (4-chlorobenzenesulfonamido) -N- [3- (2-methylimidazol-1-yl) propyl] - benzamide in the form of a white solid, melting point 122 to 123 ^° C.

The 2-amino-N- [3- (2-methylimidazol-1-yl) propyl] benzamide used as the starting material above was used in a manner similar to that in Example i (i) above for the preparation of 2-Amino-N- (3-imidazo1-1-ylpropyl) -benzamide described, prepared, but the 3-imidazol-1-yl-propylamine by 3- (2-methylimidazol-1-yl) -propylamine was replaced.

2-Amino-N- [3- (2-methylimidazol-1-yl) propyl] benzamide was isolated as an oil which was used without further purification.

Example 14 Connection N

If you work according to the above in Example 1 for the preparation of 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide described method and replacing 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide by 2-amino-N- [3- (4-methylimidazol-1-yl) -propyl] -benzamide, then 2- (4-chlorobenzenesulfonamido) -N- [3- (4-methylimidazol-1-yl) - propyl! benzamide in the form of a white solid, m.p. 123-125 ° C.

The 2-amino-N- [3- (4-methylimidazol-1-yl) propyl] benzamide used as the starting material above was prepared in a manner similar to that previously used in Example I (i) for the preparation of 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide described, but with the replacement of 3-imidazol-1-yl-propylamine by 3- (4-methylimi da zo1-1-y1) -propylamine.

2-Amino-N- [3- (4-methylimidazol-i-yl) propyl] benzamide was isolated as an oil which was used without further purification.

Example 15 Connection 0

If you work in a manner similar to that in Example 14 for the preparation of 2- (4-chlorobenzenesulfonamido) -N- [3- (4-methylimidazol-1-yl) propyl] benz- amide, but replaces 4-chlorobenzenesulfonyl chloride by 4-nitrobenzenesulfonyl chloride, so obtained one 2- (4-nitrobenzenesulfonamido) -N- [3- (4-methylimidazol-1-yl) propyl] benzamide in the form of a yellow solid, m.p. 153-155 ° C

Example 16 Connection P

38.4 g of 2- (4-nitrobenzenesulfonamido) -N- (3-iniidazol-1-yl-propyl) -benzamide were dissolved in 30 ml of glacial acetic acid and 8.0 g of 5% w / w. Palladium on activated carbon were added. The mixture was stirred for 4 hours under a hydrogen atmosphere by filtering off Catalyst freed and evaporated. The solid residue was dissolved in water and the solution by adding

- 27 -

-3 / 1

adjusted to pH 9 with aqueous ammonia. The deposited precipitate was collected and recrystallized from ethanol and gave 26.7 g of 2- (4-aminobenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide in the form of a white solid, m.p. 171-175 ° C

The 2- (4-nitrobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide used as the starting material above was produced according to Example 8.

Example 17 Connection A

1.56 g of 4-chlorobenzenesulfonyl chloride were during

2 min in 50 ml of water at 80 ⁰ C on a steam bath in portions to a solution of 1.8 g of 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide. The mixture became

Stirred for 3 h at 80 to 90 ° C., cooled to room temperature and brought to pH 7 with saturated aqueous sodium bicarbonate solution. The precipitated crude product was extracted in 2 × 100 ml dichloromethane; the resulting solution was dried over magnesium sulfate and evaporated to give a solid. The solid was recrystallized from ethanol to afford 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (1.4 g) as a white solid, mp. 174 to 176 ⁰ C.

Example 18 Connection A

3.40 g of 2- (4-chlorobenzenesulfonamido) benzoyl chloride were added in portions at room temperature to a stirred mixture of 1.29 g of 3-imidazol-1-yl-propylamine, Added 1.04 g of triethylamine and 25 ml of dimethylformamide. The temperature of the mixture rose to 33 ° C.

- 26 -

-32-

Before pouring into 500 ml of water, the mixture was Stirred for 4 h at room temperature. The aqueous solution was made from the crude product, which precipitated as a gum had been decanted. This gummy material was dissolved in 50 ml of dichloromethane, the solution dried over magnesium sulfate and evaporated. The crude product was recrystallized from ethyl acetate and gave 2.1 g of 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide in the form of a white solid, m.p. 175-177 ° C

Examples 19 to 50

If one proceeds in a manner similar to Example 1 for the preparation of 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide described, works, but with replacement of 4-chlorobenzenesulfonyl chloride and / or 2-Amino-N- (3-imidazol-1-yl-propyl) -benzamide by the indicated starting materials, so were the following compounds of general formula I were prepared (the letter of the compound is in Brackets):

19 (Q): 2- (4-Methoxybenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, m.p. 179-181 ° C): starting material, 4-methoxybenzenesulfonyl chloride;

20 (R): 2- (4-Acetamidobenzenesulfonamido) -N- (3-imidazol-i-yl-propyl) -benzamide (white solid, m.p. 192-194 ° C): starting material, 4-acetamidobenzenesulfonyl chloride;

21 (S): 2- (4-Isopropylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, m.p. 160-162 ° C): starting material, 4-isopropylbenzenesulfonyl chloride;

- 29 -

. 33 -

22 (T): 2- (4-t-Butylbenzenesulfone amido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, mp 163-166 ° C): starting material, 4-t-butylbenzenesulfonyl chloride;

23 (U): 2- (4-0ctylbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (. A white solid, m.p. 109 to 111 ⁰ C): starting material, 4-Octylbenzolsulfonylchlorid;

24 (V): 2- (4-Ethoxycarbonylbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (off-white solid, mp 156-158 ⁰ C.): Starting material, 4-Ethoxycarbonylbenzolsulfonylchlorid;

25 (W): 2- (3-trifluoromethylbenzenesulfonamido) - f> N- (3-imidazol-1-yl-propyl) -benzamide (white solid, Mp. 133 to 137 ° C): starting material, 3-trifluoromethylbenzenesulfonyl chloride;

26 (X): 2- (3,4-dichlorobenzenesulfonamido) -N- (3-L ^£ L · | imidazol-1-yl-propyl) -benzamide (white solid, m.p.

164 to 167 ^° C.): starting material, 3,4-dichlorobenzenesulfonyl chloride;

27 (Y): starting material, 2,4-dichlorobenzenesulfonyl chloride: 2- (2,4-Dichlorbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (off-white solid, mp 152-155 ⁰ C). ;

28 (Z): 2- (2,6-dichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, m.p. 203-205 ° C.): starting material, 2,6-dichlorobenzenesulfonyl chloride;

29 (AA): 2- (2,3-dichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, mp 153-155 ° C.): starting material, 2,3-dichlorobenzenesulfonyl chloride;

- 20 -

30 (BB): 2- (2-Trifluormethylbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (rehfarbener solid, m.p. 173-175 ⁰ C.): Starting material, 2-trifluoromethylbenzenesulfonyl chloride;

31 (CC): 2- (4-chloro-2-trifluoromethyl luormethy Ibenzolsulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide (off-white solid, m.p. 155 to 157 ⁰ C.): Starting material, 4 -Chlor-2-trifluoromethylbenzenesulfonyl chloride;

32 (DD), 2- (3,5-Bis-trifluormethylbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (off-white solid, mp 109 ⁰ C.): Starting material, 3,5-bis -trifluoromethylbenzenesulfonyl chloride;

33 (EE): 2- (2,4,5-Trichlorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, m.p. 190 to 200 ° C.): starting material, 2,4,5-trichlorobenzenesulfonyl chloride;

34 (FF): 2- (2,3,4-trichlorobenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide (Off-white solid, m.p. 195 to 197 ° C.): starting material, 2,3,4-trichlorobenzenesulfonyl chloride;

35 (GG): 2- (4-chloro-3-trifluormethylbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, mp 148 to 151, ^Q C.): Starting material, 4-chloro -3-trifluoromethylbenzoisulfonyl chloride;

36 (HH): 5-chloro-2- (3-trifluoromethylbenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide (White solid, m.p. 159-162 ° C): starting material, 5-chloro-2-amino-N- (3-imidazol-1-yl-propyl) -benzamide and 3-trifluoromethylbenzoisulfonyl chloride;

37 (II): 5-chloro-2- (3,5-bis-trifluoromethylbenzenesulfonamido) -N- (3-imidazo1-1-yl-propyl) -benzamide (White solid, m.p. 149-150 ° C): starting materials 5-chloro-2-amino-N- (3-imidazol-1-yl-propyl) -benzamide and 3,5-bis-trifluoromethylbenzenesulfonyl chloride ;

38 (JJ): 5-Chloro-2- (3-chlorobenzenesulfonamido) -N- (3-imidazol-i-yl-propyl) -benzamide (white solid, m.p. 124-126 ° C): starting materials 5-chloro-2-amino-N- (3-imidazol-1-yl-propyl) -benzamide and 3-chlorobenzenesulfonyl chloride;

39 (KK): 2- (3-fluorobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, m.p. 147-149 ° C): starting material 3-fluorobenzenesulfonyl chloride;

40 (LL): 2- (3-Fluoro-4-methylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, melting point 155 ° to 157 ° C.): starting material 3-fluoro-4-methylbenzenesulfonyl chloride;

41 (MM): 2- (3-Brombenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (white solid, Fp.146 to 148 ⁰ C): starting material, 3-bromobenzenesulfonyl chloride;

42 (NN): 2- (3-nitrobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (rehfarbener solid, m.p. 160-162 ⁰ C.): Starting material, 3-nitrobenzenesulfonyl chloride;

43 (00): 2- (2,4-Difluorbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (off-white solid, m.p. 122 to 124 ⁰ C.): Starting material, 2,4-difluorobenzenesulfonyl chloride;

44 (PP): 2- (3-methylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (Off-white solid, mp * 160 to 161 ° C.): starting material 3-methylbenzenesulfonyl chloride;

45 (QQ): 2- (2-Methylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (White solid, m.p. 139-141 ° C): starting material 2-methylbenzenesulfonylchlo rid;

- 52 -

46 (RR): 2- (2-Fluorbenzolsulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide (off-white solid, m.p. 115 to 117 ⁰ C.): The starting material 2-Fluorbenzolsulf onylchlorid;

47 (SS): 2- (2-chloro-5-trifluormethylbenzolsulforiamido) -N- (3-imidazol-1-yl-propyl) -benzamide (pale brown solid, m.p. 181-184 ⁰ C.): Starting material, 2-chloro- 5-trifluoromethylbenzenesulfonyl chloride;

48 (UU): 2- (4-chlorobenzenesulfonamido) -N- (4-imidazol-1-yl-butyl) benzamide (off-white solid, m.p. 131 to 133 ⁰ C.): The starting material 2-amino-N- (4 -imidazol-1-yl-butyl) -benzamide;

49 (W): 2- (4-chlorobenzenesulfonamido) -N- (2-imidazol-1-yl-ethyl) -benzamide (white solid, m.p. 130-133 ° C): starting material 2-amino-N- (2-imidazol-1 .-yl-ethyl) benzamide;

50 (WV): (+) - 2- (4-chlorobenzenesulfonamido) -N- (3-imidazol-1-yl-butyl) -benzamide (white solid, m.p. 150-153 ° C): starting material (+) - 2-amino-N- (3-imida zo1-1-yl-butyl) benzamide.

Example 51 Connection TT

A solution of 11.0 g of 2- (4-aminobenzenesulfonamido) -N- (3-imidazol-i-yl-propyl) -benzamide (prepared in Example 16) in a mixture of 9.5 ml of concentrated hydrochloric acid and 50 ml water was cooled to 0 to 5 ⁰ C while a solution of 2.09 g of sodium nitrite in 15 ml of v / ater was added dropwise while min 15th A solution of 4.58 g of potassium iodide in 10 ml of water was added over 30 minutes while maintaining a temperature of 0-10 ° C. The mixture was then heated to 95 ° C for 15 minutes. The resulting solution was prepared by adding 10% w / v dropwise.

- 35 -

aqueous sodium hydroxide solution adjusted to pH 8, where it was cooled. The solid precipitate was collected, washed with water and crystallized from ethyl acetate to give 3.4 g of 2- (4-iodobenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide in the form of a light yellow solid, m.p. 162 to 166 ° C.

Example 52 Compound W-hydrochloride

9.0 g of 2- (3-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide were dissolved in 90 ml of hot isopropanol. Then 2.0 ml of concentrated aqueous hydrochloric acid were added. The resulting solution was evaporated to give an oil which was recrystallized from ethyl acetate and 9.3 g of 2- (3-trifluoromethylbenzenesulfonamido) -N- (3-imidazol-1-yl-propyl) -benzamide hydrochloride as a white Solid, m.p. 173 to 175 ⁰ C, resulted.

Reference example 1

2-methylamino-N- (3-imidazol-1-yl-propyl) -benzamide, the can be used as a starting material was prepared as follows.

17.7 g of N-methyl isatoic anhydride were added in portions to a stirred solution of 12.5 g of 3-imidazol-1-ylpropylamine in 150 ml of dioxane over a period of 15 minutes. The mixture was stirred for a further 40 minutes before the solution was evaporated in vacuo, and 18.0 g of 2-methylamino-N- (3-imidazol-1-yl-propyl) -benzamide were obtained in the form of a buff-colored solid, m.p. 138 to 141 ⁰ C, after recrystallization from isopropanol.

- 24 -

2-methylamino-N- (3-imidazol-1-yl-propyl) -benzamide can instead of the 2-amino-N- (3-imidazol-1-ylpropyl) used as starting material in the preceding examples -benzamides are used for the preparation of corresponding compounds of general formula I,

ρ
wherein R is a methyl group.

Reference example 2

The 5-chloro-2-amino-N- (3-imidazol-1-yl-propyl) -benzamide used as starting material in Example 9 was made as follows.

26.7 g of 5-chloroisatoic anhydride were added in portions to a stirred solution of 17.2 g of 3-imidazol-1-ylpropylamine given in 150 ml of dioxane over a period of 15 min. The mixture was stirred for a further 40 minutes before the Solution was evaporated in vacuo to give 5-chloro-2-amino-N- (3-imidazol-1-yl-propyl) -benzamide as a buff solid that was used without further purification.

The 2-amino-N- (4-imidazol-1-yl-butyl) -benzamide used as a starting material in Example 48 was converted into in a similar manner as in Example i (i) above for the preparation of 2-amino-N- (3-imidazol-1-yl-propyl) -benzamide described, prepared, but 3-imidazol-1-yl-propylamine was replaced by 4-imidazol-1-yl-butylamine.

2-Amino-N- (4-imidazol-1-yl-butyl) -benzamide was isolated as an oil, which without further purification was used.

The 2-amino-N- (2-imidazol-1-yl-ethyl) -benzamide used as starting material in Example 49 was Prepared in a similar manner as in Example i (i) above for the preparation of 2-Amino-N- (3-imidazol-1-.ylpropyl) - "benzamide described, however, 3-imidazole-1 -yl-propylamine replaced by 2-imidazol-1-yl-ethylamine.

2-Amino-N- (2-imidazol-1-yl-ethyl) -benzamide was used in Isolated in the form of an oil which was used without further purification.

The (+) - 2-amino-N- (3-imidazol-1-yl-butyl) -benzamide used as starting material in Example 50 was prepared in a manner similar to that in Example i (i) above for the preparation of 2-amino-N- (3-imidazo1-1-yl-propyI) -benzamide described, but 3-imidazol-1-yl-propylamine was replaced by (+) - 3-imidazol-1-ylbutylamine replaced.

(+) - 2-Amino-N- (3-imidazol-1-yl-butyl) -benzamide was isolated as an oil which was used without further purification.

The present invention also includes within its scope pharmaceutical compositions which at least one of the compounds of general formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the present invention are administered parenterally, but are preferably administered rectally or, more preferably, used orally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions is one or more of the active compound (s) with at least an inert diluent such as starch, sucrose or lactose. The compositions can also, as is common practice, contain additional substances besides the inert diluents, e.g. Lubricants such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, Suspensions, syrups and elixirs, the inert diluents commonly used in this field, such as water and liquid paraffin. In addition to the inert diluents, such compositions also auxiliaries, such as wetting agents, suspending agents, sweeteners, flavorings, fragrances and Preservatives included. The compositions of the invention for oral administration comprise also capsules of absorbable material, such as gelatin, containing one or more of the active substances with or Contained without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile, aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspension media are propylene glycol, polyethylene glycol, Vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions can also contain auxiliaries, such as stabilizers, preservatives, Wetting agents, emulsifying agents and dispersing agents. They can be sterilized, e.g. by filtering through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiation or by heating. They can also be in the form of sterile, solid compositions are generated which in sterile water or other sterile, injectable Medium can be dissolved immediately before use.

Solid compositions for rectal administration include suppositories prepared according to known methods are formulated and one or more compounds of formula I or a pharmaceutically acceptable salt of which included.

The percentage of active ingredient in the compositions according to the invention can vary, wherein it is necessary that it constitute such a proportion that a suitable dosage will be obtained. Obviously, multiple unit dosage forms can be administered at about the same time. The applied Dose is determined by the doctor and depends on the desired therapeutic effect, the route of administration and the duration of treatment and the

Condition of the patient. In adults, the doses are generally between 0.1 and 50 mg / kg body weight / day when administered orally. For example in the treatment of diabetes between 5 and 40 mg / kg body weight / day when administered orally and as a hypolipidemic agent between 10 and 50 mg / kg body weight / day when administered orally.

The following example illustrates the pharmaceutical compositions according to the invention.

Example 53

Gelatin capsules size no.2, each containing:

mg

2- (4-chlorobenzenesulfonamido) -N- ^ imidazo 1-1-yl-propyl) -benzamide 20 Lactose 100 Starch 60 Dextrin 40 Magnesium Stearate 1

were produced according to standard methods.

Claims (6)

Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. "Koenigsberger Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun. PATENT LAWYERS APPROVED REPRESENTATIVES AT THE EUROPEAN PATENT OFFICE REPRESENTATIVES BEFORE THE EUROPEAN PATENT OFFICE Case 973 May & Baker Limited, Dagenham, Essex, England Claims Benzamide derivatives of the general formula I ) E. (D where mean: A is a divalent, straight-chain or branched-chain alkylene radical having 1 to 6 carbon atoms; R is a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl radical or an alkyl radical which is optionally substituted by fluorine; Alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyloxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino; m is an integer between 0 and 3; ρ
R is a hydrogen atom or an alkyl radical; R ^ is a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or carbamoyl radical or an alkyl radical which is optionally substituted by fluorine; Alkyloxy, alkyloxycarbonyl, dialkylamino, alkylcarbamoyl or alkanoylamino; η is an integer between 0 and 2; R is an alkyl radical and ρ is an integer between 0 and 2; as well as their pharmaceutically acceptable salts. 2. Process for the preparation of a benzamide derivative according to claim 1, characterized in that a compound of the general formula II CONH-A- (II) NH where A, R-, η and ρ are as defined in claim 1, with a sulphonating agent of the general type Formula III (R ¹ ) -SO ₂ -HaI (in) wherein R and m are as defined in claim 1 and Hal is a halogen atom, brings about the reaction, and then isolating the product obtained and optionally converting it to a pharmaceutically acceptable salt convicted. 3. Process for the preparation of a benzamide derivative according to claim 1, characterized in that a compound of the general formula IV COOH SO; (' .> ( _IV) (R ¹ Jm 1 2 ■?
wherein R »R» R »m and η are as defined in claim 1, or one of its reactive derivatives, optionally prepared in situ, with a compound of the general formula V. H ₅ NAN N (V) wherein A, R and ρ are as defined in claim 1, brings to reaction, and that the product obtained is then isolated and, if necessary, in a pharmaceutical acceptable salt transferred. 4. The method according to any one of claims 2 or 3 »characterized in that the hydroxy, amino, Alkylamino and carboxy functions, which in the 1 '3 Residues R and R ^ are contained, are protected beforehand and then released again after using the method according to claims 2 or 3. 5. A process for the preparation of a benzamide derivative according to claim 1, in the formula R or R- ^ denotes an amino radical or an iodine atom, characterized in that a derivative according to claim 1, in whose formula R or R ^ denotes a nitro radical, produced by working according to claim 2, 3 or 4 and that the nitro radical is then converted into an amino radical, and that the amino radical is optionally converted into an iodine atom by known methods. 6. Pharmaceutical composition, characterized in that that they contain at least one benzamide derivative according to claim 1 or one of its pharmaceutically acceptable ones Salts in association with at least one pharmaceutically acceptable auxiliary or coating agent contains.